The knowledge of the etiology of inherited neuromuscular disease is important for development of advanced diagnostics and rational therapeutics. The focus of this team is to determine the underlying biochemical defect in muscular dystrophies. They have found primary abnormalities of the dystrophin gene to cause more than half of all cases of muscular dystrophy. The abnormality in the 40 percent of patients with normal dystrophin is not known. Two approaches will be pursued to determine the cause of muscular dystrophies with normal dystrophin. Using a candidate gene approach, components of the extracellular matrix-membrane cytoskeleton complex (adhalin, integrin alpha7, merosin and 3 dystroglycans) will be analyzed by RT-PCR screens. Secondly, a genome- wide linkage analysis is proposed in a 29-member pedigree showing a dominant limb-girdle muscular dystrophy that is not allelic to other limb-girdle dystrophy loci identified to date. It is suggested that this research should contribute significantly to understanding of the muscular dystrophies, both at the molecular and clinical levels. These studies should result in improved diagnosis of patients with muscular dystrophy and offer new pathways for rational therapeutics.